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RH Incompatibility

Rh incompatibility occurs when an Rh-negative mother carries an Rh-positive fetus, leading to the production of antibodies that can destroy fetal red blood cells, causing hemolytic disease of the fetus and newborn. Effective immunoprophylaxis for at-risk mothers is crucial for prevention, and intrauterine fetal transfusion can be a life-saving treatment for affected fetuses. The document provides an overview of the condition, its epidemiology, diagnosis, management, and guidelines.

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RH Incompatibility

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Rh incompatibility

Straight to the point of care

Last updated: Apr 11, 2025

Table of Contents
Overview 3
Summary 3
Definition 3

Theory 4
Epidemiology 4
Aetiology 4
Pathophysiology 5
Classification 5
Case history 5

Diagnosis 7
Approach 7
History and exam 10
Risk factors 10
Investigations 12
Differentials 15

Management 18
Approach 18
Treatment algorithm overview 23
Treatment algorithm 24
Emerging 29
Patient discussions 29

Follow up 30
Monitoring 30
Complications 31
Prognosis 31

Guidelines 32
Diagnostic guidelines 32
Treatment guidelines 32

Evidence tables 34

References 36

Images 43

Disclaimer 46
Rh incompatibility Overview

Summary
Rhesus (Rh) incompatibility is a condition where an Rh-negative mother carrying an Rh-positive fetus can
produce antibodies against paternally derived Rh antigens on fetal red blood cells. These antibodies can

OVERVIEW
cross the placenta, and destroy fetal red blood cells. It is a leading cause of haemolytic disease of the fetus
and newborn, also known as erythroblastosis fetalis.

Effective immunoprophylaxis of Rh-negative at-risk mothers is key to primary prevention.

Intrauterine fetal transfusion is a life-saving treatment for severely affected fetuses.

Survival rates are more than 90%.

Definition
Rh incompatibility occurs in an Rh-negative mother carrying an Rh-positive fetus. If the mother is exposed
to the paternally derived Rh antigens on fetal red blood cells (RBCs) she can become sensitised and
produce immunoglobulin G (IgG) antibodies, usually against the RhD antigen. These maternally derived
antibodies can then freely cross the placenta, binding to and destroying fetal RBCs. This is a leading cause
of haemolytic disease of the fetus and newborn (HDN or HDFN, also known as erythroblastosis fetalis),
which involves progressive fetal anaemia, and, if untreated, may ultimately lead to hydrops fetalis (collection
of fluid in serous compartments) and death.[1][2]

Epidemiology
About 15% of the white population has an RhD-negative blood type.[3] Population data suggest that the
incidence of RhD negativity is highest among Basques (36%).[3] Around 6% to 7% of black people and less
THEORY

than 1% of American Indian and Asian people have an RhD-negative blood type.[3] [4] Rh alloimmunisation
due to RhD has declined markedly as immunoprophylaxis has become routine practice.[5] [6] Societal
factors, such as delayed childbearing and smaller families, may also have contributed to this decline.[5]

In the UK, about 16% of the white population is RhD-negative.[7] In 2013-2014, about 15% of births in
England were to RhD-negative women; about 40% of these women had an RhD-negative fetus.[8]

The estimated global prevalence of Rh haemolytic disease is 276/100,000 live births; in countries with well-
established perinatal-neonatal care, the prevalence is approximately 2.5/100,000 live births.[9] One survey
in Canada estimated that 8/100,000 infants are affected by maternal anti-D antibodies.[10] In the US, the
reported incidence of Rh haemolytic disease ranges from 1.0 to 6.8/1000 live births; the higher rate may
reflect improved identification and reporting of sensitised women and increasing prevalence of atypical, non-
RhD antibodies for which immunoprophylaxis regimens are unavailable.[11] [12] [13]

The relative frequency has been reported for several of these non-RhD antibodies.[11] In a large prospective
series including over 300,000 consecutive patients, about 1% of pregnant women had alloantibodies
detected in the first trimester.[14] Of these, the prevalence of alloantibodies other than anti-D was
328/100,000, of which 191/100,000 implied a risk for occurrence of haemolytic disease of the fetus and
newborn as the father carried the antigen. The most common non-anti-D antibodies were anti-K and anti-
c.[14]

Aetiology
Three genes are thought to encode for the Rh blood groups. Two of these genes are located on the short
arm of chromosome 1: RhD and RhCE.[15] Study of the RhD gene has revealed significant heterogeneity
that may result in a lack of expression of the RhD phenotype. RhD pseudogene has all 10 exons of the RhD,
but the gene is not transcribed into a messenger RNA product due to the presence of a stop codon in the
intron between exons 3 and 4. Therefore, no RhD protein is synthesised, and the patient is serologically
RhD-negative.[16]

Rh incompatibility is caused by destruction of fetal red blood cells (RBCs) from transplacental passage
of maternally derived immunoglobulin G antibodies. Passage of fetal cells into the maternal circulation
and fetomaternal haemorrhage (FMH) is a frequent occurrence, detectable in 65% of pregnancies either
antenatally or in the early postnatal period.[17] Sensitisation of an RhD-negative mother with as little as 0.1
mL of RhD-positive fetal RBCs may elicit a primary immune response.[17] [18] [19]

Placental trauma of varying degrees may lead to sensitising FMH. FMH increases throughout pregnancy
(3% first trimester, 43% second trimester, and 64% third trimester).[17] [18] [19] FMH has been found
in 1% to 6% of external cephalic versions.[20] [21] [22] Small amounts of FMH (>0.1 mL) are potentially
immunising and occur in 2% of patients undergoing amniocentesis.[23] [24] The incidence of FMH at the
time of chorionic villus sampling is about 14%.[25] Other invasive procedures, such as cordocentesis, can
also cause FMH. Primary prevention of RhD sensitisation can be accomplished with appropriate use of RhD
immunoprophylaxis in these clinical settings.[23]

4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 11, 2025.
BMJ Best Practice topics are regularly updated and the most recent version of the topics
can be found on [Link] . Use of this content is subject to our disclaimer (.
Use of this content is subject to our) . © BMJ Publishing Group Ltd 2025. All rights reserved.
Rh incompatibility Theory
An episode of threatened, spontaneous, or induced abortion can sensitise RhD-negative patients, but
the risk of RhD alloimmunisation is very low with pregnancy loss before 12 weeks’ gestation.[26] [27]
Alloimmunisation has been reported after ectopic pregnancy, and 24% of patients with ruptured ectopic
pregnancy have fetal RBCs detectable in the maternal circulation.[28] The risk of RhD alloimmunisation is

THEORY
low in complete molar pregnancy because of absent or incomplete vascularisation of villi and absence of D
antigen. Conversely, a partial mole should be viewed as a risk factor for sensitisation.[23][26] [29]

Pathophysiology
Exposure of an RhD-negative mother to RhD-positive fetal red blood cells (RBCs) results in the generation
of B lymphocyte clones that recognise the foreign RBC antigen and promote production of immunoglobulin
G (IgG). Memory B lymphocytes await the reappearance of RBCs containing the respective antigen, usually
in a subsequent pregnancy. When challenged by these antigenic RBCs, the lymphocytes differentiate
into plasma cells and produce IgG. Maternal IgG crosses the placenta and attaches to fetal RBCs that
have expressed the antigen. These RBCs are then sequestered by macrophages in the fetal spleen,
where extravascular haemolysis occurs, producing fetal anaemia. The fetus attempts to compensate by
increasing extramedullary haematopoiesis. This results in hepatosplenomegaly, portal hypertension, cardiac
compromise, tissue hypoxia, hypoviscosity, and increased brain perfusion. Extreme fetal haemoglobin
deficits of ≥70 g/L (≥7 g/dL) can ultimately lead to hydrops fetalis (collection of fluid in serous compartments)
and intrauterine fetal death, unless corrected by intrauterine fetal transfusion or neonatal exchange
transfusion following delivery.[17] [26] [30]

Classification
Clinical classification[2]
• Rhesus D (RhD) red blood cell (RBC) alloimmunisation
• Haemolysis caused by RhD antigen
• Non-RhD RBC alloimmunisation
• Haemolysis caused by other, atypical RBC antigens (Kell, Rhc, Kidd, Duffy)

Case history
Case history #1
A 32-year-old woman presents at 25 weeks' gestation in her third pregnancy with a positive antibody
screen. She is known to be Rh-negative with an Rh-positive partner. Two previous children were
born overseas: the first child was carried to term and is healthy. The second child, also born at term,
underwent phototherapy in the immediate neonatal period due to jaundice. The patient did not have anti-D
prophylaxis given antenatally or postnatally in the previous pregnancies. Physical examination is normal.

Case history #2
A 38-year-old primigravida woman presents for routine antenatal care. Her blood type is known to be Rh-
negative with a negative indirect Coombs test, and her partner is Rh-positive. She has been counselled

Manifestations of severe erythroblastosis fetalis include ultrasound evidence of significant effusions

in serous cavities, organomegaly, polyhydramnios, and extensive skin oedema (anasarca). Anti-RhD
antibody titres in severe disease are usually high (>1:32 dilutions). Anti-Kell antibodies may be associated
with profound fetal anaemia and hydrops in the presence of low antibody titres due to suppression of
erythropoiesis. Evidence suggesting severe fetal anaemia includes high peak systolic velocities on
Doppler ultrasound of the middle cerebral artery, low biophysical profile scores, and a sinusoidal fetal
heart rate pattern. Although these manifestations of severe fetal disease are usually not detected in a
first affected pregnancy, significant fetomaternal haemorrhage from any cause may lead to a secondary
immune response and hydrops fetalis, even in a primiparous patient.

6 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 11, 2025.
BMJ Best Practice topics are regularly updated and the most recent version of the topics
can be found on [Link] . Use of this content is subject to our disclaimer (.
Use of this content is subject to our) . © BMJ Publishing Group Ltd 2025. All rights reserved.
Rh incompatibility Diagnosis

Approach
In Rh-negative pregnant women, where Rh paternal phenotype is positive or unknown, the possibility of them
becoming alloimmunised and producing red cell antibodies should be considered. Laboratory testing for the
presence of red cell antibodies is confirmatory.

Clinical evaluation
All RhD-negative pregnant women (where the fetus has an Rh-positive father) are at potential risk for
alloimmunisation and erythroblastosis. Risk factors for maternal sensitisation to RhD antigen include:
history of an Rh-positive fetus to an Rh-negative mother; invasive fetal procedures; fetomaternal
haemorrhage; placental trauma; spontaneous, threatened, or induced abortion; omission (or inadequate
dosing) of appropriate Rh immunoprophylaxis following a potentially immunising obstetric event in a
previous or current pregnancy; and multiparity.

Accurate maternal history taking is an important step in evaluating potential risk of sensitisation or fetal
anaemia in a current pregnancy. Inquiry should begin with questioning about previous pregnancies,
paternal phenotype (if known), history of blood transfusion, administration of Rh immunoprophylaxis, and
obstetric and neonatal outcome of all pregnancies.

Although the primary maternal immune response to sensitisation by the D antigen is usually weak, it
may be greatly enhanced when a secondary immune response is generated by antigenic challenge
in a subsequent pregnancy. Hence, the risk for fetal anaemia and immune fetal hydrops (abnormal
accumulation of fluid in 2 or more fetal compartments) increases with increasing parity.[2] [26] [31] When
hydrops has occurred in a previous pregnancy, it is likely to occur again, and at an earlier gestational age.
Once hydrops or a stillbirth has occurred due to anti-D antibodies from Rh incompatibility, the estimated
chance of intrauterine death of a subsequent RhD-positive fetus is 90% if untreated.[32]

Laboratory investigations
Blood type and antibody screening

DIAGNOSIS
At the first antenatal visit, all women are screened for ABO blood group, Rh type, and the presence of red
blood cell (RBC) antibodies.[23] [33] Repeated RhD-antibody testing for all unsensitised RhD-negative
women is also recommended at 24-28 weeks’ gestation, unless the biological father is known to be
RhD-negative.[33] A positive red blood cell antibody screen in an Rh-negative mother demands further
investigation, including identification of the antibody and measurement of the titre.

An identifiable Rh antibody screen in an Rh-negative mother should prompt paternal phenotyping

and genotyping (if paternity is certain). A father with Rh-positive blood may be homozygous or
heterozygous for the D antigen. If the latter, the risk of transmission of the RhD gene (and hence the risk
of Rh incompatibility) to the fetus is 50%, compared with 100% if he is homozygous. In the case of a
heterozygous RhD-positive, or unknown, paternal genotype, fetal Rh type is determined by genetic testing
of amniotic fluid cells or it can be estimated using cell-free fetal DNA in the maternal circulation, which
may be helpful in mothers who refuse amniocentesis.[34] [35]

In sensitised patients the maternal serum antibody titre is a guide to disease severity. The American
College of Obstetricians and Gynecologists states that a critical titre (titre associated with a significant
risk for severe haemolytic disease of the fetus and newborn, and hydrops) is considered to be between
1:8 and 1:32 in most centres.[34] If the initial antibody titre is 1:8 or less, the patient may be monitored

Assessing fetomaternal haemorrhage

A rosette test can be used to rule out significant fetomaternal haemorrhage. If results are positive,
a Kleihauer-Betke (acid elution) test or flow cytometry can measure the amount of fetal blood in the
maternal circulation. Such assessments may be carried out in a variety of circumstances, including in
unsensitised Rh-negative mothers carrying an RhD-positive fetus (or when fetal RhD status is unknown)
following birth; sensitising events occurring after 20 weeks’ gestation; or events potentially associated with
placental trauma and disruption of the fetomaternal interface (e.g., placental abruption, blunt trauma to
the abdomen, cordocentesis, placenta praevia with bleeding).[23][29] [36]

Fetal ultrasound and blood sampling

Fetal anaemia due to Rh incompatibility can be diagnosed by measuring peak systolic velocity in the
middle cerebral artery (MCA). The prediction of moderate to severe anaemia by Doppler ultrasound has a
sensitivity of 100% and false-positive rate of 12%.[31] [37] Elevated blood flow velocity for gestational age
should prompt percutaneous umbilical blood sampling (if anaemia is strongly suspected).

Fetal blood sampling through umbilical cord venepuncture (cordocentesis) or the intrahepatic vein allows
direct measurement of the fetal haemoglobin and haematocrit.

Definitive information on the severity of anaemia will direct appropriate and life-saving fetal therapy
through intrauterine fetal transfusion.[38]

Ultrasound examination of the fetus at risk for Rh incompatibility may reveal subcutaneous oedema,
ascites, pleural effusion, or pericardial effusion, all of which are consistent with severe fetal anaemia in an
affected fetus.[39]

Non-invasive screening for fetal anaemia with Doppler ultrasound has supplanted serial amniocentesis
for spectrophotometry in developed countries, but may not be available in all other regions. Where used,
DIAGNOSIS

spectral analysis of amniotic fluid at optical density 450 nanometres (AOD450) measures the level of
bilirubin as an indirect indicator of fetal haemolysis. Liley proposed a management scheme involving three
zones based on gestational age between 27 and 42 weeks. When used to monitor fetal disease, serial
procedures are undertaken at 10-day to 2-week intervals and continued until delivery.[16] Queenan and
co-workers proposed a modified AOD450 curve between 14 weeks and 40 weeks. The Queenan curve
has shown better predictive value than the Liley curve in severe anaemia.[30]

8 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 11, 2025.
BMJ Best Practice topics are regularly updated and the most recent version of the topics
can be found on [Link] . Use of this content is subject to our disclaimer (.
Use of this content is subject to our) . © BMJ Publishing Group Ltd 2025. All rights reserved.
Rh incompatibility Diagnosis

Increased velocity in the middle cerebral artery consistent with severe fetal anaemia
The Ottawa Hospital; used with consent of the patient

DIAGNOSIS

Fetal hydrops, with ascites and hepatomegaly (arrow) diagnosed on antenatal ultrasound
The Ottawa Hospital; used with consent of the patient

History and exam

Key diagnostic factors
DIAGNOSIS

presence of risk factors (common)

• Strong risk factors for maternal sensitisation to RhD antigen include: history of delivery of an Rh-
positive fetus to an Rh-negative mother; fetomaternal haemorrhage; invasive fetal procedures;
placental trauma; abortion (threatened, spontaneous, or induced); omission (or inadequate dosing) of
appropriate Rh immunoprophylaxis following a potentially immunising obstetric event in a previous or
current pregnancy; and multiparity.

Risk factors
Strong
history of an RhD-positive fetus in an RhD-negative mother
• RhD antigen is highly immunogenic. Only RhD-positive fetuses, from RhD-positive fathers, sensitise
their RhD-negative mothers to produce anti-D antibodies.

10 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 11, 2025.
BMJ Best Practice topics are regularly updated and the most recent version of the topics
can be found on [Link] . Use of this content is subject to our disclaimer (.
Use of this content is subject to our) . © BMJ Publishing Group Ltd 2025. All rights reserved.
Rh incompatibility Diagnosis
fetomaternal haemorrhage
• Fetomaternal haemorrhage (FMH) is common and detectable in 65% of pregnancies either antenatally
or in the early postnatal period.[17] RhD antigen is 50 times more immunogenic than other Rh
antigens. Sensitisation of an RhD-negative mother with as little as 0.1 mL of RhD-positive fetal red
blood cells (RBCs) may elicit a primary immune response.[23]

invasive fetal procedures

• Small amounts of FMH (>0.1 mL) are potentially immunising and occur in 2% of patients undergoing
amniocentesis.[23] [24] The incidence of FMH at the time of chorionic villus sampling is about
14%.[25] Other invasive procedures, such as cordocentesis, can also cause FMH.

placental trauma
• Placental trauma of varying degrees may lead to sensitising FMH.

abortion
• An episode of threatened, spontaneous, or induced abortion can sensitise RhD-negative women, but
the risk of RhD alloimmunisation is very low with pregnancy loss before 12 weeks’ gestation.[27]

multiparity
• Although the primary maternal immune response to sensitisation by the D antigen is usually weak, it
may be greatly enhanced when a secondary immune response is generated by antigenic challenge
in a subsequent pregnancy. Hence, the risk for fetal anaemia and hydrops increases with increasing
parity.[2] [26] [31]

omission of Rh immunoprophylaxis
• Omission (or inadequate dosing) of appropriate Rh immunoprophylaxis following potentially sensitising
obstetric events, such as unrecognised FMH, in a previous or current pregnancy can lead to maternal
sensitisation to the D antigen.

Weak

DIAGNOSIS
external cephalic version
• A meta-analysis of 17 studies found FMH (as detected by Kleihauer-Betke test) in 1% of women after
external cephalic version.[22]

molar pregnancy
• Risk of RhD alloimmunisation is low in complete molar pregnancy because of absent or incomplete
vascularisation of villi and absence of D antigen. Conversely, a partial mole should be viewed as a risk
factor for sensitisation.[23][26] [29]

ectopic pregnancy
• Alloimmunisation has been reported after ectopic pregnancy, and 24% of patients with ruptured
ectopic pregnancy have fetal RBCs detectable in the maternal circulation.[28]

Investigations
1st test to order

Test Result
maternal blood type Rh-negative
• All Rh-negative pregnant women are at potential risk for
alloimmunisation and erythroblastosis.
maternal serum Rh antibody screen positive screen
• Positive red blood cell antibody screen must prompt further
investigation for possible alloimmunisation due to Rh antibodies.[16]
DIAGNOSIS

12 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 11, 2025.
BMJ Best Practice topics are regularly updated and the most recent version of the topics
can be found on [Link] . Use of this content is subject to our disclaimer (.
Use of this content is subject to our) . © BMJ Publishing Group Ltd 2025. All rights reserved.
Rh incompatibility Diagnosis

Other tests to consider

Test Result
maternal serum antibody titre critical titre: between 1:8
and 1:32 (may vary among
• As methods vary between laboratories performing this test, each
laboratories)
should report the titre below which severe fetal Rh incompatibility is
unlikely and above which further investigations and monitoring are
indicated.[38]
• The maternal serum antibody titre is a guide to disease severity.
The American College of Obstetricians and Gynecologists states
that a critical titre (titre associated with a significant risk for severe
haemolytic disease of the fetus and newborn, and hydrops) is
considered to be between 1:8 and 1:32 in most centres.[34] If the
initial antibody titre is 1:8 or less, the patient may be monitored with
titre assessment every 4 weeks.[34] However, serial titres are not
adequate for monitoring fetal status when the mother has had a
previously affected fetus or neonate.[34]
paternal blood type Rh-positive
• An Rh-positive partner of an Rh-negative mother creates blood group
incompatibility in the fetus.
paternal zygosity homozygous or
heterozygous
• Heterozygosity denotes a 50% risk of the offspring having an Rh-
negative blood type and no risk of Rh incompatibility. Homozygosity
denotes a 100% chance of an Rh-positive fetus, at risk of Rh
incompatibility. Zygosity is determined by assay of plasma DNA in the
case of RhD; serological testing of paternal red cells can be used for
analysis of other red cell antigen systems.
fetal ultrasound may show subcutaneous
oedema, ascites, pleural
• Fluid in serous cavities of the fetus is easily detected with
effusion, or pericardial
ultrasonography.[32] [37] [39] [40]
• These findings are consistent with severe fetal anaemia in an affected effusion
fetus.[39]

DIAGNOSIS

Fetal hydrops, with ascites and hepatomegaly

(arrow) diagnosed on antenatal ultrasound
The Ottawa Hospital; used with consent of the patient

Test Result
Doppler velocimetry of fetal middle cerebral artery (peak systolic ≥1.5 MoM
velocity)
• Measured Doppler sonography with estimation of peak systolic
velocity in the fetal middle cerebral artery (MCA) can be used to
predict moderate to severe anaemia in the fetus. MCA peak systolic
velocity is increased in fetuses with significant anaemia. Elevated
blood flow velocity for gestational age should prompt percutaneous
umbilical blood sampling (if anaemia is strongly suspected).[37]

Increased velocity in the middle cerebral

artery consistent with severe fetal anaemia
The Ottawa Hospital; used with consent of the patient
fetal blood typing (from amniocentesis or maternal circulation) Rh type
• If the father is heterozygous RhD-positive, or paternity is uncertain,
the fetus' RhD type is determined by genetic testing of amniotic fluid
DIAGNOSIS

cells or it can be estimated using cell-free fetal DNA in the maternal

circulation.[35]
direct assessment of fetal anaemia fetal haemoglobin and
haematocrit
• Through umbilical cord venepuncture (cordocentesis) or the
intrahepatic vein.
• If fetal haemoglobin is within 20 g/L (2 g/dL) (i.e., 2 standard
deviations) of gestational age norms and direct antiglobulin test is
positive, the fetus is only mildly affected. Haemoglobin deficit of 20-70
g/L (2-7 g/dL) suggests moderate anaemia. Fetal anaemia is severe
with haemoglobin deficits >70 g/L (>7 g/dL).
roset te test may be positive
• A rosette test can be used to rule out significant fetomaternal
haemorrhage.
Kleihauer-Betke test/flow cytometry variable
• Can measure the amount of fetal blood in the maternal circulation.

14 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 11, 2025.
BMJ Best Practice topics are regularly updated and the most recent version of the topics
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Rh incompatibility Diagnosis

Differentials

Condition Differentiating signs / Differentiating tests

symptoms
Non-immune fetal hydrops • Hydrops fetalis consists of • Maternal serum antibodies
generalised subcutaneous are negative in non-immune
oedema and fluid collections fetal hydrops. There are
in some or all serous more than 80 causes of fetal
cavities. hydrops.
• Placental calcification, • Non-immune hydrops
oligohydramnios, and carries a high rate of infant
intrauterine growth mortality, and in many
restrictions may be patients (17%) its cause
associated with congenital remains indeterminate after
infections.[40] [41] diagnostic work-up.[39]

Parvovirus infection • History of environmental • Viral-specific IgM appears

exposure to parvovirus may about 10 to 12 days after
arouse suspicion of possible infection. Fetal infection
infection in asymptomatic is confirmed by analysing
people. amniotic fluid, cord blood, or
• Symptoms include maternal serous fluid for viral DNA or
fever, myalgia, coryza, RNA by polymerase chain
headache, nausea, reaction.[42]
and erythematous,
maculopapular exanthema
on the trunk and limbs.
Arthropathy and arthritis are
also common in women and
adolescents.
• Progressive fetal anaemia,
due to preferential
destruction of immature red
blood cells (RBCs) by the

DIAGNOSIS
virus, leads to hydrops and
intrauterine fetal death.[31]
[42]

Non-RhD haemolytic • Usually transfusion-induced. • Serum antibodies can be

disease The mechanism for fetal detected in the maternal
anaemia is haemolysis and blood. Although the titre is
erythroid suppression. not as reliable as in RhD
• Prior obstetric history disease, severe disease is
does not reliably predict unusual with titres <1:32,
occurrence in subsequent with the exception of anti-Kell
pregnancy, and maternal antibodies where significant
antibody titre does not fetal disease can occur at
correlate with severity.[2] much lower titres.
• Kell alloimmunisation is the • Middle cerebral artery
most common non-RhD (MCA) Doppler should be
haemolytic disease, with an performed and has been
incidence of 0.1% to 0.2% in shown to be reliable for fetal
the obstetric population.[2] anaemia detection.
• Fetal haemoglobin should be
assessed by cordocentesis
when non-invasive

Condition Differentiating signs / Differentiating tests

symptoms
testing (MCA Doppler) is
abnormal.[2]

Placental chorioangioma • May be present in up to 1% • A solid placental mass is

of pregnancies.[31] detected by standard 2-
• Large placental masses dimensional sonography,
of ≥5 cm may produce and colour Doppler
complications such as fetal sonography reveals a
anaemia, hydrops, and pulsatile mass.
polyhydramnios, and poor • Maternal serum alpha-
perinatal outcome.[31] fetoprotein may be high in
association with a placental
chorioangioma. Doppler
velocimetry of the MCA
may be consistent with fetal
anaemia.[43]

Fetomaternal • Severe, acute fetomaternal • Peak systolic velocity on

haemorrhage haemorrhage may be MCA Doppler may be
entirely asymptomatic or increased.
manifest as a reduction in • Kleihauer-Betke test
perceived fetal movements (persistence of fetal RBCs
by the mother. Clinical in maternal serum after
symptoms are usually non- denaturation by strong acid)
specific. or flow cytometry is also
helpful.[31]

Twin-twin transfusion • Develops in association • Ultrasound findings include

syndrome (TTTS) with monochorionic twin polyhydramnios in one twin
placentation, usually (recipient), and amniotic sac
between 15 and 26 and oligohydramnios in the
weeks' gestation. It is other (donor).
found in 5.5% to 17.5% • Growth of fetuses is usually
of all monochorionic discordant.[44]
DIAGNOSIS

pregnancies.[44] • Hydrops may develop in

later stages of the disease,
usually in the recipient co-
twin.
• Perinatal mortality may
reach 80% to 100% when
untreated.[44]

Twin anaemia- • Develops in monochorionic • Absence of ultrasound

polycythemia sequence twins and is characterised finding of twin
(TAPS) by a large intertwin oligohydramnios (donor) and
haemoglobin difference polyhydramnios (recipient)
without the abnormal sequence.
amniotic fluid seen in TTTS. • Peak systolic velocity on
• Results mainly due to slow MCA Doppler: donor >1.5
intertwin blood transfusion MoM (anaemia); recipient
leading to anaemia for the <1.0 MoM (polycythemia).
donor and polycythemia for
the recipient.
• Can occur spontaneously
(3% to 5%) or after laser

16 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 11, 2025.
BMJ Best Practice topics are regularly updated and the most recent version of the topics
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Rh incompatibility Diagnosis

Condition Differentiating signs / Differentiating tests

symptoms
surgery for TTTS (2% to
13%).[45]

Screening
At the first antenatal visit, ABO blood type, RhD type, and red blood cell (RBC)-antibody screening is
recommended for all pregnant women.[23] [33] Repeated RhD-antibody testing for all unsensitised RhD-
negative women is also recommended at 24-28 weeks’ gestation, unless the biological father is known to be
RhD-negative.[33]

DIAGNOSIS

Approach
The prevention of RhD sensitisation in Rh-negative mothers carrying an Rh-positive fetus is the primary
management objective. It involves immunoprophylaxis via the administration of anti-D immunoglobulin (also
known as Rho(D) immune globulin in some countries) to at-risk women.

If sensitisation does occur, the window for primary prevention is effectively closed and Rh
immunoprophylaxis is no longer appropriate. Actions then involve fetal and maternal surveillance for, and
management of, fetal anaemia or hydrops.

Prevention of RhD sensitisation

Immunoprophylaxis with anti-D immunoglobulin is highly effective in preventing sensitisation of Rh-
negative mothers carrying an Rh-positive fetus.[23][26] [46] It has been instrumental in the dramatic
reduction in death from Rh incompatibility. Anti-D immunoglobulin is a blood product containing a high
titre of antibodies to Rh antigens of red blood cells. Its precise mechanism of action is unknown, but it
may work by neutralising Rh-positive fetal red blood cells in the maternal blood, thus reducing the risk of
sensitisation. Administration is efficacious by either the intramuscular or intravenous route.[47] Anti-Rh
antibodies persist for more than 3 months after one dose.

A prerequisite for immunoprophylaxis is knowledge of the maternal rhesus status.[46] All pregnant women
should be tested at the time of the first antenatal visit for RhD type, and screened for the presence
of anti-D antibodies, to identify unsensitised RhD-negative patients who are potential candidates for
immunoprophylaxis.[23] [46] Anti-D immunoglobulin is not given to an RhD-negative mother who is
already sensitised to the RhD antigen.

Eligible candidates should receive routine ante- and postnatal administration of anti-D immunoglobulin,
as described below. In addition, the risk of sensitisation can be reduced by administering anti-D
immunoglobulin to women in situations in which fetomaternal haemorrhage (FMH) is likely, such as
miscarriage, chorionic villus sampling, and amniocentesis.[7] Multiple clinical guidelines describing RhD
sensitisation prevention strategies have been published, including those from the American College
of Obstetricians and Gynecologists, and the International Federation of Gynecology and Obstetrics/
International Confederation of Midwives.[23] [46]

Routine postnatal administration of anti-D immunoglobulin

RhD sensitisation occurs in approximately 16% of pregnancies among RhD-negative women.[46]
Postnatal administration of anti-D immunoglobulin reduces this risk to approximately 1.5%, and is the
most effective intervention to prevent Rh incompatibility in subsequent pregnancies.[23] [46]

Following birth, newborns from RhD-negative women should have their Rh factor determined from
umbilical-cord blood.[46] If the infant is confirmed to be RhD-positive, all RhD-negative women who are
not known to be sensitised should receive anti-D immunoglobulin (intravenously or intramuscularly) within
72 hours of delivery.[23][29][46]
MANAGEMENT

Guidelines vary on the dose of anti-D immunoglobulin that should be administered, and can depend on
the size of the FMH, the brand of anti-D immunoglobulin used, and affordability.[46] A prophylactic dose
of 1500 IU (equivalent to 300 micrograms) of anti-D immunoglobulin is commonly given in high-income
countries and can prevent RhD sensitisation after exposure to up to 30 mL of RhD-positive fetal whole
blood or 15 mL of fetal red cells.[23] [46] [48] On rare occasions, delivery-associated FMH may be greater

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Rh incompatibility Management
than 30 mL. Circumstances such as traumatic deliveries, caesarean sections, manual removal of the
placenta, delivery of twins, and unexplained hydrops fetalis are more likely to be associated with a large
FMH. Accordingly, several guidelines, including those from the American College of Obstetricians and
Gynecologists, and from the British Society for Haematology, recommend that RhD-negative women
who give birth to RhD-positive infants should undergo additional testing to assess the volume of FMH
and guide the amount of anti-D immunoglobulin required to prevent sensitisation.[23][36] [49] However,
at no time should anti-D immunoglobulin treatment be delayed pending the results of quantitative FMH
testing.[50]

If anti-D immunoglobulin is not given within 72 hours of delivery, it should be given as soon as the need is
recognised, for up to 28 days after delivery.[29]

Routine antenatal administration of anti-D immunoglobulin

Building on the efficacy of postnatal anti-D immunoglobulin administration, the risk of RhD sensitisation
in Rh-negative women carrying an Rh-positive baby has been shown to be further reduced (to
approximately 0.5%) by the introduction of routine antenatal administration.[46] [51]

Routine antenatal antibody screening should be obtained at 28 weeks of gestation before administration
of anti-D immunoglobulin (to identify women who have become sensitised before 28 weeks of
gestation).[23] [29][36] [52] If anti-D antibodies are identified, it should be determined whether this
presence is immune-mediated or passive (e.g., as a result of previous anti-D immunoglobulin treatment).
If RhD antibodies are passive, then the woman should continue to be offered prophylaxis with anti-D
immunoglobulin; however, if they are present because of sensitisation, prophylaxis is not beneficial, and
management should proceed in accordance with protocols for RhD-sensitised pregnancies.[23]

Prophylactic antenatal anti-D immunoglobulin should be offered to unsensitised RhD-negative women,

whether the fetal blood type is unknown or known to be Rh-positive.[23] [29] The American College of
Obstetricians and Gynecologists recommends that a single dose be offered at 28 weeks of gestation,
while other guidelines recommend either a single dose at around 28 weeks, or two doses at around 28
and 34 weeks of gestation.[23] [29][36][46]

Non-invasive estimation of fetal Rh status is now possible via the analysis of cell-free DNA in maternal
plasma, and this method may be acceptable for sensitised patients who refuse amniocentesis.[35]
Some countries recommend employing this technique in the first trimester, to allow targeted antenatal
RhD immunoprophylaxis (i.e., only where the fetus is RhD-positive); however, the American College of
Obstetricians and Gynecologists does not recommend the routine use of this approach on the grounds of
cost-effectiveness.[23] [46] When paternity is certain, rhesus testing of the baby’s father may be offered
as a means of determining fetal RhD status.[29] [35]

Routine antenatal anti-D immunoglobulin prophylaxis should be administered regardless of, and in
addition to, any anti-D immunoglobulin that may have been given for a potentially sensitising event (see
below).[36] In the past, it has been recommended that a second dose of anti-D immunoglobulin should
be administered to women who have not given birth at 40 weeks; however, the current guidelines suggest
that this is generally not required, provided that the antenatal injection was given no earlier than 28 weeks'
MANAGEMENT

gestation.[23] [29]

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19
can be found on [Link] . Use of this content is subject to our disclaimer (.
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Rh incompatibility Management
Administration of anti-D immunoglobulin following potentially
sensitising events
In RhD-negative, previously unsensitised women, a variety of events associated with potential placental
trauma or disruption of the fetomaternal interface can lead to sensitising FMH during pregnancy. Anti-D
immunoglobulin can help minimise the risk of such sensitisation, and if indicated, should be administered
as soon as possible after the event, ideally within 72 hours.[29] [36] If anti-D immunoglobulin is not
given within 72 hours, it should be given as soon as the need is recognised, for up to 28 days after
the potentially sensitising event.[29] For sensitising events occurring after 20 weeks of pregnancy, the
magnitude of FMH should be assessed, and further doses of anti-D immunoglobulin administered if
required.[36] [50]

Miscarriage/abortion and intrauterine fetal death

Guidelines for the administration of anti-D immunoglobulin following miscarriage/abortion vary and
local protocols should be followed.[23][29] [36] [46] [50] [53] The American College of Obstetricians and
Gynecologists states that in the case of spontaneous first-trimester miscarriage or abortion in RhD-
negative women, the risk of sensitisation is very low so routine Rh testing and Rh immunoprophylaxis
is not recommended. However, Rh testing and administration of anti-D immunoglobulin may be
considered on an individual basis, according to patient preferences.[23] [27] It recommends that anti-D
immunoglobulin should be given to unsensitised RhD-negative women who have a pregnancy termination
(either medical or surgical); or who experience fetal death in the second or third trimester.[23] [27]

Guidelines from the International Federation of Gynecology and Obstetrics/International Confederation of

Midwives note that because an intrauterine fetal death may have been caused by a large FMH, it may be
useful to perform a Kleihauer–Betke test, to determine the size of the haemorrhage, and thus the dose of
anti-D immunoglobulin needed.[46]

Ectopic pregnancy

Several guidelines recommend the administration of anti-D immunoglobulin for all cases of ectopic
pregnancy in unsensitised RhD-negative women.[23][29] [46] However, in the UK, National Institute for
Health and Care Excellence (NICE) guidelines recommend that anti-D immunoglobulin should only be
administered to Rh-negative women who have surgical management of an ectopic pregnancy (and not
those who have solely medical management).[53]

Molar pregnancy

In a complete molar pregnancy, sensitisation to RhD should not occur, due to the absence of fetal organ
development. However, the situation is different in a partial molar pregnancy. Because differentiating
between the forms of molar pregnancy may be difficult, it is generally advised to administer anti-D
immunoglobulin to all unsensitised RhD-negative women with a molar pregnancy.[23] [46]

Invasive procedures (e.g., chorionic villus sampling, amniocentesis)

Most countries recommend administration of anti-D immunoglobulin following invasive diagnostic

MANAGEMENT

procedures, such as chorionic villus sampling or amniocentesis, in unsensitised RhD-negative women

when the fetuses could be RhD-positive.[23][29] [36] [46]

Bleeding and abdominal trauma in pregnancy

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Rh incompatibility Management
Anti-D immunoglobulin is recommended for RhD-negative women who experience antenatal
haemorrhage after 20 weeks of gestation; some guidelines also suggest anti-D immunoglobulin should be
considered in certain cases of bleeding earlier in gestation.[23][36] [46]

Anti-D immunoglobulin should be administered to RhD-negative women who have experienced abdominal
trauma.[23][29] [36] [46]

Quantitative testing for FMH may be considered following events potentially associated with placental
trauma and disruption of the fetomaternal interface (e.g., placental abruption, blunt trauma to the
abdomen, cordocentesis, placenta praevia with bleeding).[29] There is a substantial risk of FMH over 30
mL with such events.[29]

External cephalic version in breech presentation

Some guidelines recommend administration of anti-D immunoglobulin for unsensitised RhD-negative

patients following external cephalic version.[23] [29] [36] Quantitative testing for FMH may also be
considered.[29]

Verbal or written consent must be obtained prior to administration of anti-D immunoglobulin.

Management following RhD sensitisation

If antibody screening identifies anti-D antibodies in an RhD-negative pregnant woman, and assessments
conclude that their presence is active, not passive, the patient should be considered sensitised,
and specialist obstetric advice should be sought.[50] Rh immunoprophylaxis is no longer given.[34]
Fortunately, initial sensitisation in a first affected pregnancy is often mild.

The initial management of an RhD-sensitised pregnancy involves the determination of the paternal
rhesus status. If paternity is certain, and the father is RhD-negative, no further assessment/intervention
is necessary. All children from a homozygous RhD-positive father, and 50% from a heterozygous RhD-
positive father, will be RhD-positive.[34] In the case of a heterozygous RhD-positive, or unknown, paternal
genotype, the fetal antigen type should be assessed (by amniocentesis or non-invasive analysis of
maternal blood).[34] In the case of an RhD-positive fetus, management involves fetal and maternal
surveillance for signs of fetal anaemia and hydrops.

Quantitation of maternal antibody titre is performed serially to document worsening disease and identify
the need for additional fetal testing and/or treatment. The American College of Obstetricians and
Gynecologists states that a critical titre (titre associated with a significant risk for severe haemolytic
disease of the fetus and newborn, and hydrops) is considered to be between 1:8 and 1:32 in most
centres.[34] If the initial antibody titre is 1:8 or less, the patient may be monitored with titre assessment
every 4 weeks.[34] However, serial titres are not adequate for monitoring fetal status when the mother
has had a previously affected fetus or neonate.[34] In the UK, the Royal College of Obstetricians and
Gynaecologists recommends anti-D antibodies should be measured every 4 weeks up to 28 weeks of
gestation and then every 2 weeks until delivery, and referral to a fetal medicine specialist should occur
if there are rising antibody levels, if the level reaches the specific threshold of >4 IU/mL, or if ultrasound
features are suggestive of fetal anaemia.[52]
MANAGEMENT

In a centre with trained personnel and when the fetus is at an appropriate gestational age, Doppler
measurement of peak systolic velocity in the fetal middle cerebral artery is an appropriate non-invasive
means to monitor pregnancies complicated by RhD sensitisation.[34] Fetal ultrasound assessment is also
employed.

Fetal therapy
The goal of fetal therapy is to correct severe anaemia, ameliorate tissue hypoxia, prevent (or reverse) fetal
hydrops, and avoid fetal death.

If fetal blood is Rh-negative, or if middle cerebral artery blood flow or amniotic bilirubin levels remain
normal in an Rh-positive fetus, the pregnancy can continue to term untreated. If fetal blood is Rh-
positive or of unknown Rh status, and middle cerebral artery flow or amniotic bilirubin levels are elevated,
suggesting fetal anaemia, the fetus can be given intravascular intrauterine blood transfusions by a
specialist at an institution equipped to care for high-risk pregnancies.

Intraperitoneal transfusion; the echogenic needle tip is visualised in the pocket of ascites
The Ottawa Hospital; used with consent of the patient

Neonatal therapy
Neonates with erythroblastosis are immediately evaluated by a paediatrician to determine the need for
MANAGEMENT

exchange transfusion, phototherapy, or intravenous immunoglobulin (IVIG). IVIG is used in some clinical
practice as it has been shown to reduce the need for exchange transfusion in neonates with proven
haemolytic disease due to Rh and/or ABO incompatibility and to decrease the duration of hospitalisation

22 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 11, 2025.
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Rh incompatibility Management
and phototherapy.[54] [55] However, there is an overall lack of evidence to support its use for the
treatment of alloimmune haemolytic disease.[56] [57] [Evidence C]

Treatment algorithm overview

Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

Initial ( summary )
unsensitised RhD-negative mother

1st anti-D immunoglobulin

sensitising event: plus additional anti-D immunoglobulin

miscarriage/abortion and
intrauterine fetal death

sensitising event: ectopic plus additional anti-D immunoglobulin

pregnancy

sensitising event: molar plus additional anti-D immunoglobulin

pregnancy

sensitising event: plus additional anti-D immunoglobulin

invasive procedures
(e.g., chorionic villus
sampling, amniocentesis)

sensitising event: plus additional anti-D immunoglobulin

bleeding/abdominal
trauma in pregnancy

sensitising event: plus additional anti-D immunoglobulin

external cephalic version
in breech presentation

sensitised RhD-negative mother

1st seek specialist obstetric advice

Acute ( summary )
neonate with erythroblastosis

1st paediatric evaluation

MANAGEMENT

Treatment algorithm
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

Initial
unsensitised RhD-negative mother

unsensitised RhD-negative 1st anti-D immunoglobulin

mother
Primary options

» anti-D immunoglobulin: consult specialist

for guidance on dose

» Routine antenatal administration: anti-D

immunoglobulin (also known as Rho(D) immune
globulin in some countries) administered
whether fetal blood type is unknown, or
known to be RhD-positive. Single dose at
28 weeks’ gestation (either intravenously
or intramuscularly).[23] Some guidelines
recommend a single dose at around 28 weeks,
or two doses at around 28 and 34 weeks of
gestation.[29] [36] [46]

» Routine postnatal administration: anti-

D immunoglobulin administered (either
intravenously or intramuscularly) in women who
have given birth to Rh-positive infants within
72 hours of delivery.[23][29] [46] The size of
fetomaternal haemorrhage should be assessed,
and further doses of anti-D immunoglobulin
administered if required.[23] [36]

» The dose can vary depending on local

guidelines, and factors such as brand of anti-D
immunoglobulin.
sensitising event: plus additional anti-D immunoglobulin
miscarriage/abortion and
Treatment recommended for ALL patients in
intrauterine fetal death
selected patient group
Primary options

» anti-D immunoglobulin: consult specialist

for guidance on dose

» Additional anti-D immunoglobulin

administration should not be given routinely
following spontaneous miscarriage or abortion
in the first trimester.[23] However, it may be
considered on an individual basis, according to
MANAGEMENT

patient preferences.[23] [27]

» Anti-D immunoglobulin administration is

recommended following pregnancy termination
(either medical or surgical); or fetal death in the
second or third trimester.[23] [27]

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Rh incompatibility Management

Initial
» Dose should be given within 72 hours
of occurrence.[29] [36] The dose can vary
depending on local guidelines, and factors such
as brand of anti-D immunoglobulin.

» For sensitising events occurring after 20 weeks

of pregnancy, size of fetomaternal haemorrhage
should be assessed, and further doses of anti-D
immunoglobulin administered if required.[36] [50]

» Guidelines for anti-D immunoglobulin

administration vary; follow local protocols.
sensitising event: ectopic plus additional anti-D immunoglobulin
pregnancy
Treatment recommended for ALL patients in
selected patient group
Primary options

» anti-D immunoglobulin: consult specialist

for guidance on dose

» Additional anti-D immunoglobulin

administration is recommended following all
cases of ectopic pregnancy.[23] UK guidelines
recommend that anti-D immunoglobulin should
only be administered to Rh-negative women
who have surgical management of an ectopic
pregnancy (and not those who have solely
medical management).[53]

» Dose should be given within 72 hours of

identification.[23] [29] [36] The dose can vary
depending on local guidelines, and factors such
as brand of anti-D immunoglobulin.

» Guidelines for anti-D immunoglobulin

administration vary; follow local protocols.
sensitising event: molar plus additional anti-D immunoglobulin
pregnancy
Treatment recommended for ALL patients in
selected patient group
Primary options

» anti-D immunoglobulin: consult specialist

for guidance on dose

» Additional anti-D immunoglobulin is advised to

be administered in all molar pregnancies (due to
the difficulty in differentiating between complete
and partial forms).[23] [46]
MANAGEMENT

» Dose should be given within 72 hours of

identification.[29] [36] The dose can vary
depending on local guidelines, and factors such
as brand of anti-D immunoglobulin.

Initial
sensitising event: plus additional anti-D immunoglobulin
invasive procedures
Treatment recommended for ALL patients in
(e.g., chorionic villus
selected patient group
sampling, amniocentesis)
Primary options

» anti-D immunoglobulin: consult specialist

for guidance on dose

» Additional anti-D immunoglobulin

administration is recommended following
invasive diagnostic procedures such as chorionic
villus sampling or amniocentesis.[23]

» Dose should be given within 72 hours

of occurrence.[29] [36] The dose can vary
depending on local guidelines, and factors such
as brand of anti-D immunoglobulin.

» If carried out after 20 weeks of pregnancy,

size of fetomaternal haemorrhage should
be assessed, and further doses of anti-D
immunoglobulin administered if required.[36] [50]
sensitising event: plus additional anti-D immunoglobulin
bleeding/abdominal
Treatment recommended for ALL patients in
trauma in pregnancy
selected patient group
Primary options

» anti-D immunoglobulin: consult specialist

for guidance on dose

» Additional anti-D immunoglobulin is

recommended for antenatal haemorrhage
after 20 weeks of gestation, and abdominal
trauma.[23]

» Dose should be given within 72 hours

of occurrence.[29] [36] The dose can vary
depending on local guidelines, and factors such
as brand of anti-D immunoglobulin.

» Consider quantitative testing for fetomaternal

haemorrhage following events occurring after
20 weeks, or those potentially associated
with placental trauma and disruption of the
fetomaternal interface (e.g., placental abruption,
blunt trauma to the abdomen, cordocentesis,
placenta praevia with bleeding).[29] Administer
further doses of anti-D immunoglobulin if
required.[36]
MANAGEMENT

sensitising event: plus additional anti-D immunoglobulin

external cephalic version
Treatment recommended for ALL patients in
in breech presentation
selected patient group
Primary options

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Rh incompatibility Management

Initial
» anti-D immunoglobulin: consult specialist
for guidance on dose

» Additional anti-D immunoglobulin

administration is recommended following
external cephalic version.[23] Quantitative
testing for fetomaternal haemorrhage may also
be considered.[29]

» Dose should be given within 72 hours

of occurrence.[29] [36] The dose can vary
depending on local guidelines, and factors such
as brand of anti-D immunoglobulin.
sensitised RhD-negative mother

1st seek specialist obstetric advice

» If antibody screening identifies anti-D

antibodies in an RhD-negative pregnant
woman, and assessments conclude that their
presence is active, not passive, the patient
should be considered sensitised, and specialist
obstetric advice should be sought.[50] Rh
immunoprophylaxis is no longer given.[34]

» The initial management of an RhD-sensitised

pregnancy involves the determination of the
paternal rhesus status. If paternity is certain,
and the father is RhD-negative, no further
assessment/intervention is necessary. All
children from a homozygous RhD-positive father
will be RhD-positive, and there is a 50% risk
of children from a heterozygous RhD-positive
father being RhD-positive.[34] In the case of
a heterozygous RhD-positive, or unknown,
paternal genotype, the fetal antigen type should
be assessed (by genetic testing of amniotic fluid
cells or using cell-free fetal DNA in the maternal
circulation).[34] [35] In the case of an RhD-
positive fetus, management involves fetal and
maternal surveillance for signs of fetal anaemia
and hydrops.

» Quantitation of maternal antibody titre is

performed serially to document worsening
disease and identify the need for additional fetal
testing and/or treatment. The American College
of Obstetricians and Gynecologists states that
a critical titre (titre associated with a significant
risk for severe haemolytic disease of the fetus
and newborn, and hydrops) is considered to be
MANAGEMENT

between 1:8 and 1:32 in most centres.[34] If

the initial antibody titre is 1:8 or less, the patient
may be monitored with titre assessment every
4 weeks.[34] However, serial titres are not
adequate for monitoring fetal status when the
mother has had a previously affected fetus or

Initial
neonate.[34] In the UK, the Royal College of
Obstetricians and Gynaecologists recommends
anti-D antibodies should be measured every
4 weeks up to 28 weeks of gestation and then
every 2 weeks until delivery, and referral to a
fetal medicine specialist should occur if there
are rising antibody levels, if the level reaches the
specific threshold of >4 IU/mL, or if ultrasound
features are suggestive of fetal anaemia.[52]

» In a centre with trained personnel and when

the fetus is at an appropriate gestational age,
Doppler measurement of peak systolic velocity in
the fetal middle cerebral artery is an appropriate
non-invasive means to monitor pregnancies
complicated by RhD sensitisation.[34] Fetal
ultrasound assessment is also employed.

» The goal of fetal therapy is to correct severe

anaemia, ameliorate tissue hypoxia, prevent (or
reverse) fetal hydrops, and avoid fetal death.

» If fetal middle cerebral artery flow or amniotic

bilirubin levels are elevated, suggesting fetal
anaemia, the fetus can be given intravascular
intrauterine blood transfusions by a specialist
at an institution equipped to care for high-risk
pregnancies.

Acute
neonate with erythroblastosis

1st paediatric evaluation

Primary options

» normal immunoglobulin human: consult

specialist for guidance on dose

» Neonates with erythroblastosis are

immediately evaluated by a paediatrician to
determine the need for exchange transfusion,
phototherapy, or intravenous immunoglobulin.
MANAGEMENT

28 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 11, 2025.
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Rh incompatibility Management

Emerging
Nipocalimab
Nipocalimab is a next-generation Fc receptor inhibitor, inhibiting immunoglobulin G (IgG) transport across
the placenta (including the transfer of anti-red cell alloantibodies). A multicentre phase 2 study is ongoing
to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of nipocalimab in pregnant
women at high risk for early onset severe haemolytic disease of the fetus and newborn.[58] Nipocalimab has
been granted rare paediatric disease designation and orphan drug designation by the US Food and Drug
Administration for the prevention of haemolytic disease of the fetus and newborn.

Maternal therapy with plasmapheresis and/or intravenous

immunoglobulin (IVIG)
Limited data, including isolated case reports, have supported the use of maternal plasmapheresis and/or
IVIG in severe cases of maternal alloimmunisation in early gestation to reduce maternal antibody load and
temporise, until a time in gestational age when intravascular fetal transfusion can be safely accomplished
(i.e., >20 weeks). Limited reports of direct fetal treatment with IVIG suggest a possible role for this approach
in selected patients.[59] [60] [61]

Patient discussions
Mothers should be counselled regarding the importance of fetal movement as a screening tool for fetal
health and of decreased fetal movement as a symptom of developing fetal hydrops.

MANAGEMENT

Monitoring
Monitoring
FOLLOW UP

Patients should be instructed about the need for monitoring the neonate and infant for signs and
symptoms of anaemia. Infants affected by Rh incompatibility, even those successfully treated in utero,
may develop late anaemia commencing 1 week to 3 months after birth, due to the continued presence
of circulating antibody-coated fetal red blood cells that continue to be haemolysed. The importance of
neonatal follow-up cannot be overemphasised, with assessments of the infant's haemoglobin once or
twice a week until 3 months of life.[63]

30 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 11, 2025.
BMJ Best Practice topics are regularly updated and the most recent version of the topics
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Rh incompatibility Follow up

Complications

Complications Timeframe Likelihood

FOLLOW UP
hyperbilirubinaemia and kernicterus short term high

Encephalopathy, athetoid cerebral palsy, and/or sensorineural deafness may result from deposition of
bilirubin into the basal ganglia.

Postnatal treatment consists of intensive phototherapy and exchange transfusions to reduce bilirubin levels
and prevent kernicterus.

transfusion-related fetal bradycardia short term low

The most common complication of intrauterine transfusion is fetal bradycardia during transfusion (8%).[65]
Fetal bradycardia and vasospasm are more frequent when accidental intra-arterial transfusion is given.
Immediate interruption of the transfusion is therapeutic in most cases.

transfusion-related neurodevelopmental long term low

abnormalities

Although short-term neurological outcome is normal in >90% of infants, neurodevelopmental abnormalities

have been reported in a few studies with small patient numbers.[63] In one study, 4.8% of the children
treated by intrauterine transfusion developed neurodevelopmental impairment. Fetal hydrops was the
strongest predictor for impaired outcome.[66]

fetal and neonatal hydrops variable high

Hydrops fetalis is defined as abnormal accumulation of fluid in two or more fetal compartments. It is a
major fetal complication in RhD disease that will develop when a haemoglobin deficit of 70 g/L (7 g/dL) is
exceeded.

Hydrops fetalis is diagnosed with ultrasound. Intrauterine fetal transfusion is life-saving and can reverse
fetal hydrops. Cardiac decompensation is often seen in hydrops.[63] Perinatal mortality in fetal hydrops is
50%.[64]

neonatal anaemia variable high

Characterised by reduced reticulocyte count and low serum erythropoietin levels.

Diagnosed when haemoglobin falls <8 g/dL and is treated with transfusion. Erythropoietin has been used
to prevent anaemia and reduce transfusions. Iron supplementation is not recommended.[63]

Prognosis

Without immunoprophylaxis, haemolytic disease of the newborn recurs in 88% of pregnancies where the
fetus is Rh-positive.[62]

Diagnostic guidelines

United Kingdom

High-throughput non-invasive prenatal testing for fetal RHD genotype (ht tps://
[Link]/guidance/dg25)
Published by: National Institute for Health and Care Excellence Last published: 2016

Treatment guidelines

United Kingdom

Ectopic pregnancy and miscarriage: diagnosis and initial management

(ht tps://[Link]/guidance/ng126)
GUIDELINES

Published by: National Institute for Health and Care Excellence Last published: 2023

Blood transfusions in obstetrics (Green-top guideline no. 47) (ht tps://

[Link]/guidance/browse-all-guidance/green-top-guidelines)
Published by: Royal College of Obstetricians and Gynaecologists Last published: 2015

The management of women with red cell antibodies during pregnancy (Green-
top guideline no. 65) (ht tps://[Link]/guidance/browse-all-guidance/
green-top-guidelines)
Published by: Royal College of Obstetricians and Gynaecologists Last published: 2014

BCSH guideline for the use of anti-D immunoglobulin for the prevention of
haemolytic disease of the fetus and newborn (ht tps://[Link]/guidelines/?
category=Transfusion&fromdate=&todate=)
Published by: British Committee for Standards in Haematology Last published: 2014
(updated 2023)

Routine antenatal anti-D prophylaxis for women who are rhesus D negative
(ht tps://[Link]/guidance/TA156)
Published by: National Institute for Health and Care Excellence Last published: 2008

International

FIGO/ICM guidelines for preventing Rhesus disease: a call to action (ht tps://
[Link]/doi/full/10.1002/ijgo.13459)
Published by: International Federation of Gynecology and Obstetrics; Last published: 2021
International Confederation of Midwives; Worldwide Initiative for Rhesus
Disease Eradication

32 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 11, 2025.
BMJ Best Practice topics are regularly updated and the most recent version of the topics
can be found on [Link] . Use of this content is subject to our disclaimer (.
Use of this content is subject to our) . © BMJ Publishing Group Ltd 2025. All rights reserved.
Rh incompatibility Guidelines

North America

ACOG clinical practice update: paternal and fetal genotyping in the

management of alloimmunization in pregnancy (ht tps://[Link]/
clinical)
Published by: American College of Obstetricians and Gynecologists Last published: 2024

ACOG clinical practice update: Rh D immune globulin administration

after abortion of pregnancy loss at less than 12 weeks of gestation (ht tps://
[Link]/clinical)
Published by: American College of Obstetricians and Gynecologists Last published: 2024

Prevention of Rh alloimmunisation (ht tps://[Link]/article/

S1701-2163(17)31111-8/fulltext)
Published by: Society of Obstetricians and Gynaecologists of Canada Last published: 2018

GUIDELINES
ACOG practice bulletin no. 192: management of alloimmunization during
pregnancy (ht tps://[Link]/clinical)
Published by: American College of Obstetricians and Gynecologists Last published: 2018
(reaffirmed 2024)

ACOG practice bulletin no. 181: prevention of Rh D alloimmunization (ht tps://

[Link]/clinical)
Published by: American College of Obstetricians and Gynecologists Last published: 2017
(reaffirmed 2024)

Red blood cell transfusions in newborn infants (ht tps://[Link]/en/

documents/authors-auteurs/fetus-and-newborn-commit tee)
Published by: Canadian Paediatric Society Last published: 2014
(reaffirmed 2020)

Oceania

Prophylactic use of RhD immunoglobulin in pregnancy care (ht tps://

[Link]/anti-d-0)
Published by: Royal Australian and New Zealand College of Last published: 2021
Obstetricians and Gynaecologists; National Blood Authority, Australia

Evidence tables
What are the benefits and harms of immunoglobulin for neonates with
EVIDENCE TABLES

alloimmune haemolytic disease/jaundice?

This table is a summary of the analysis reported in a Cochrane Clinical Answer that focuses on the
above important clinical question.

View the full source Cochrane Clinical Answer ([Link]

doi/10.1002/cca.2095/full)

Evidence C * Confidence in the evidence is very low or low where GRADE has been performed
and the intervention may be more effective/beneficial than the comparison for key
outcomes. However, this is uncertain and new evidence could change this in the
future.

Population: Newborn infants with alloimmune haemolytic disease

Intervention: Intravenous immunoglobulin (IVIG)
Comparison: Placebo or no treatment

† ‡
Outcome Effectiveness (BMJ rating) Confidence in evidence (GRADE)

Use of exchange transfusion Favours intervention Very Low

Exchange transfusions per Favours intervention Very low

infant

Use of top‐up transfusion (in No statistically significant Low

first week) difference

Use of top‐up transfusion (after No statistically significant Very low

first week) difference

Top‐up transfusions per infant No statistically significant GRADE assessment not performed for
(in first week and after first difference this outcome
week)

Maximum total serum bilirubin Favours intervention Very low

Duration of phototherapy Favours intervention GRADE assessment not performed for

this outcome

Longer‐term neurological See note ᵃ GRADE assessment not performed for

outcomes (1 to > 2 years) this outcome

Adverse effects See note ᵇ GRADE assessment not performed for

this outcome

34 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 11, 2025.
BMJ Best Practice topics are regularly updated and the most recent version of the topics
can be found on [Link] . Use of this content is subject to our disclaimer (.
Use of this content is subject to our) . © BMJ Publishing Group Ltd 2025. All rights reserved.
Rh incompatibility Evidence tables
† ‡
Outcome Effectiveness (BMJ rating) Confidence in evidence (GRADE)

Neonatal mortality - None of the studies identified by the

EVIDENCE TABLES
review assessed this outcome

Note
The Cochrane review which underpins this Cochrane Clinical Answer (CCA) stated that the methods of only
two of the nine included studies were robust enough to guide routine clinical practice, and that the quality
of the evidence as assessed by GRADE was all low to very low. Therefore, they concluded that there is
insufficient evidence to support the routine use of IVIG in infants with alloimmune haemolytic disease.

ᵃ Results reported narratively; two RCTs (204 infants) reported no cases of kernicterus, deafness or cerebral
palsy, while a third RCT (80 infants) reported that neurodevelopmental outcome at aged ≥ 2 years was the
same in those treated with IVIG and those treated with placebo.

ᵇ Results reported narratively; no adverse effects were reported in the IVIG group (9 RCTs; 658 infants).
Sixteen infants across 6 RCTs were reported to have hypoglycaemia, hypocalcaemia, sepsis (with or without
brain abscess), and inspissated bile syndrome, due to exchange transfusion.

* Evidence levels
The Evidence level is an internal rating applied by BMJ Best Practice. See the EBM Toolkit (https://
[Link]/info/evidence-tables/) for details.

Confidence in evidence

A - High or moderate to high

B - Moderate or low to moderate
C - Very low or low

† Effectiveness (BMJ rating)

Based on statistical significance, which demonstrates that the results are unlikely to be due to chance, but
which does not necessarily translate to a clinical significance.

‡ Grade certainty ratings

High The authors are very confident that the true

effect is similar to the estimated effect.
Moderate The authors are moderately confident that
the true effect is likely to be close to the
estimated effect.
Low The authors have limited confidence in the
effect estimate and the true effect may be
substantially different.
Very Low The authors have very little confidence in
the effect estimate and the true effect is
likely to be substantially different.
BMJ Best Practice EBM Toolkit: What is GRADE? ([Link]
is-grade/)

Key articles
• Brennand J, Cameron A. Fetal anaemia: diagnosis and management. Best Pract Res Clin Obstet
REFERENCES

Gynaecol. 2008 Feb;22(1):15-29. Abstract ([Link]

tool=[Link])

• American College of Obstetrics and Gynecology. ACOG practice bulletin no. 181: prevention of Rh D
alloimmunization. Obstet Gynecol. 2017 Aug;130(2):e57-70. Abstract ([Link]
pubmed/28742673?tool=[Link])

• American Congress of Obstetrics and Gynecology. ACOG practice bulletin no. 192: management
of alloimmunization during pregnancy. Obstet Gynecol. 2018 Mar;131(3):e82-90. Abstract (http://
[Link]/pubmed/29470342?tool=[Link])

• Qureshi H, Massey E, Kirwan D, et al. BCSH guideline for the use of anti-D immunoglobulin for the
prevention of haemolytic disease of the fetus and newborn. Transfus Med. 2014 Feb;24(1):8-20. Full
text ([Link] Abstract ([Link]
pubmed/25121158?tool=[Link])

• Visser GHA, Thommesen T, Di Renzo GC, et al. FIGO/ICM guidelines for preventing Rhesus disease:
a call to action. Int J Gynaecol Obstet. 2021 Feb;152(2):144-7. Full text ([Link]
pmc/articles/PMC7898700) Abstract ([Link]
tool=[Link])

References
1. Hadley AG. In vitro assays to predict the severity of hemolytic disease of the newborn. Transfus
Med Rev. 1995 Oct;9(4):302-13. Abstract ([Link]
tool=[Link])

2. Brennand J, Cameron A. Fetal anaemia: diagnosis and management. Best Pract Res Clin Obstet
Gynaecol. 2008 Feb;22(1):15-29. Abstract ([Link]
tool=[Link])

3. Mourant AE, Kopec AC, Domaniewska-Sobczak K. The distribution of the human blood groups and
other biochemical polymorphisms. 2nd ed. London: Oxford University Press; 1976.

4. Kanko TK, Woldemariam MK. Prevalence of Rhesus D negativity among reproductive age women in
Southern Ethiopia: a cross-sectional study. BMC Womens Health. 2021 Apr 19;21(1):161. Full text
([Link] Abstract ([Link]
pubmed/33874938?tool=[Link])

5. Joseph KS, Kramer MS. The decline in Rh hemolytic disease: should Rh prophylaxis get all the
credit? Am J Public Health. 1998 Feb;88(2):209-15. Full text ([Link]

36 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 11, 2025.
BMJ Best Practice topics are regularly updated and the most recent version of the topics
can be found on [Link] . Use of this content is subject to our disclaimer (.
Use of this content is subject to our) . © BMJ Publishing Group Ltd 2025. All rights reserved.
Rh incompatibility References
doi/pdf/10.2105/AJPH.88.2.209) Abstract ([Link]
tool=[Link])

REFERENCES
6. Van der Schoot CE, Soussan AA, Koelewijn J, et al. Non-invasive antenatal RHD typing. Transfus
Clin Biol. 2006 Mar-Apr;13(1-2):53-7. Abstract ([Link]
tool=[Link])

7. National Institute for Health and Care Excellence. Routine antenatal anti-D prophylaxis for women who
are rhesus D negative. Aug 2008 [internet publication]. Full text ([Link]
TA156)

8. National Institute for Health and Care Excellence. High-throughput non-invasive prenatal testing for
fetal RHD genotype. Nov 2016 [internet publication]. Full text ([Link]

9. Bhutani VK, Zipursky A, Blencowe H, et al. Neonatal hyperbilirubinemia and Rhesus disease of the
newborn: incidence and impairment estimates for 2010 at regional and global levels. Pediatr Res.
2013 Dec;74(1 suppl):86-100. Full text ([Link]
Abstract ([Link]

10. Baker JM, Campbell DM, Pavenski K, et al. Infants affected by Rh sensitization: a 2-year Canadian
National Surveillance Study. Paediatr Child Health. 2021 Jun;26(3):159-65. Full text (https://
[Link]/pmc/articles/PMC8077204) Abstract ([Link]
pubmed/33936335?tool=[Link])

11. Chavez GF, Mulinare J, Edmonds LD. Epidemiology of Rh hemolytic disease of the newborn in
the United States. JAMA. 1991 Jun 26;265(24):3270-4. Abstract ([Link]
pubmed/1904504?tool=[Link])

12. Martin JA, Hamilton BE, Sutton PD, et al. Births: final data for 2003. Natl Vital Stat Rep. 2005 Sep
8;54(2):1-116. Full text ([Link] Abstract (http://
[Link]/pubmed/16176060?tool=[Link])

13. Ling L, Yu D, Gleeson CD, et al. 968 Estimation of hemolytic disease of the newborn in the United
States from 1996-2010. Am J Obstet Gynecol. 2021 Feb;224(2 suppl):S600-1. Full text (https://
[Link]/article/S0002-9378(20)32369-3/fulltext)

14. Koelewijn JM, Vrijkotte TG, van der Schoot CE, et al. Effect of screening for red cell antibodies,
other than anti-D, to detect hemolytic disease of the fetus and newborn: a population study in
the Netherlands. Transfusion. 2008 May;48(5):941-52. Abstract ([Link]
pubmed/18248570?tool=[Link])

15. Cherif-Zahar B, Mattei MG, Le Van Kim C, et al. Localization of the human Rh blood
group gene structure to chromosome region 1p34.3-1p36.1 by in situ hybridization. Hum
Genet. 1991 Feb;86(4):398-400. Abstract ([Link]
tool=[Link])

16. Moise KJ. Red blood cell alloimmunization in pregnancy. Semin Hematol. 2005 Jul;42(3):169-78.
Abstract ([Link]

18. Bowman JM. The prevention of Rh immunization. Transfus Med Rev. 1988 Sep;2(3):129-50. Abstract
([Link]

19. Bowman JM. The management of Rh-Isoimmunization. Obstet Gynecol. 1978 Jul;52(1):1-16. Abstract
([Link]

20. Boucher M, Marquette GP, Varin J, et al. Fetomaternal hemorrhage during external cephalic version.
Obstet Gynecol. 2008 Jul;112(1):79-84. Abstract ([Link]
tool=[Link])

21. Marcus RG, Crewe-Brown H, Krawitz S, et al. Feto-maternal haemorrhage following successful and
unsuccessful attempts at external cephalic version. Br J Obstet Gynaecol. 1975 Jul;82(7):578-80.
Abstract ([Link]

22. Grootscholten K, Kok M, Oei SG, et al. External cephalic version-related risks: a meta-analysis.
Obstet Gynecol. 2008 Nov;112(5):1143-51. Abstract ([Link]
tool=[Link])

23. American College of Obstetrics and Gynecology. ACOG practice bulletin no. 181: prevention of Rh D
alloimmunization. Obstet Gynecol. 2017 Aug;130(2):e57-70. Abstract ([Link]
pubmed/28742673?tool=[Link])

24. Bowman JM, Pollock JM. Transplacental fetal hemorrhage after amniocentesis. Obstet Gynecol. 1985
Dec;66(6):749-54. Abstract ([Link]

25. Blakemore KJ, Baumgarten A, Schoenfeld-Dimaio M, et al. Rise in maternal serum alpha-fetoprotein
concentration after chorionic villus sampling and the possibility of isoimmunization. Am J Obstet
Gynecol. 1986 Nov;155(5):988-93. Abstract ([Link]
tool=[Link])

26. Urbaniak SJ, Greiss MA. RhD haemolytic disease of the fetus and the newborn. Blood Rev. 2000
Mar;14(1):44-61. Abstract ([Link]

27. American College of Obstetricians and Gynecologists. ACOG clinical practice update: Rh D immune
globulin administration after abortion or pregnancy loss at less than 12 weeks of gestation. Obstet
Gynecol. 2024 Dec 1;144(6):e140-3. Abstract ([Link]
tool=[Link])

28. Katz J, Marcus RG. The risk of Rh isoimmunization in ruptured tubal pregnancy. Br Med J.
1972 Sep 16;3(5828):667-9. Full text ([Link]
pdf/[Link]) Abstract ([Link]
tool=[Link])

29. Fung KFK, Eason E. No. 133: prevention of Rh alloimmunization. J Obstet Gynaecol Can. 2018
Jan;40(1):e1-10. Abstract ([Link]

38 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 11, 2025.
BMJ Best Practice topics are regularly updated and the most recent version of the topics
can be found on [Link] . Use of this content is subject to our disclaimer (.
Use of this content is subject to our) . © BMJ Publishing Group Ltd 2025. All rights reserved.
Rh incompatibility References
30. Moise KJ Jr. Hemolytic disease of the fetus and newborn. In: Creasy RK, Resnik R, Iams JD, et al,
eds. Creasy and Resnik's maternal-fetal medicine: principles and practice. 6th ed. Philadelphia, PA:
Saunders; 2008:479-503.

REFERENCES
31. Oepkes D, Adama van Scheltema P. Intrauterine fetal transfusion in the management of fetal anemia
and fetal thrombocytopenia. Semin Fetal Neonatal Med. 2007 Dec;12(6):432-8. Abstract (http://
[Link]/pubmed/17706475?tool=[Link])

32. Bowman JM. Intrauterine and neonatal transfusion. In: Anderson KC, Ness PM, eds. Scientific basis of
transfusion medicine: implications for clinical practice. London, UK: WB Saunders; 1994:403-20.

33. US Preventive Services Task Force. Rh(D) incompatibility: screening. Feb 2004 [internet publication].
Full text ([Link]
screening)

34. American Congress of Obstetrics and Gynecology. ACOG practice bulletin no. 192: management
of alloimmunization during pregnancy. Obstet Gynecol. 2018 Mar;131(3):e82-90. Abstract (http://
[Link]/pubmed/29470342?tool=[Link])

35. American College of Obstetricians and Gynecologists. Clinical practice update: paternal and
fetal genotyping in the management of alloimmunization in pregnancy. Obstet Gynecol. June
4 2024;144(2):e47-9. Full text ([Link]
acog_clinical_practice_update__paternal_and_fetal.[Link])

36. Qureshi H, Massey E, Kirwan D, et al. BCSH guideline for the use of anti-D immunoglobulin for the
prevention of haemolytic disease of the fetus and newborn. Transfus Med. 2014 Feb;24(1):8-20. Full
text ([Link] Abstract ([Link]
pubmed/25121158?tool=[Link])

37. Mari G, Deter RL, Carpenter RL, et al. Noninvasive diagnosis by Doppler ultrasonography of
fetal anemia due to maternal red-cell alloimmunization. N Engl J Med. 2000 Jan 6;342(1):9-14.
Full text ([Link] Abstract (http://
[Link]/pubmed/10620643?tool=[Link])

38. Abdel-Fattah S, Soothill P. Assessing the severity of haemolytic disease of the fetus and newborn:
clinical aspects. In: Hadley A, Soothill P, eds. Alloimmune disorders of pregnancy: anaemia,
thrombocytopenia and neutropenia in the fetus and newborn. Cambridge, UK: Cambridge University
Press; 2002:153-72.

39. Bellini C, Hennekam RC, Bonioli E. A diagnostic flow chart for non-immune hydrops fetalis. Am J
Med Gen A. 2009 May;149A(5):852-3. Abstract ([Link]
tool=[Link])

40. Trainor B, Tubman R. The emerging pattern of hydrops fetalis: incidence, aetiology and management.
Ulster Med J. 2006 Sep;75(3):185-6. Full text ([Link]
PMC1891778) Abstract ([Link]

42. Tolfvenstam T, Broliden K. Parvovirus B19 infection. Semin Fetal Neonatal Med.
2009 Aug;14(4):218-21. Abstract ([Link]
tool=[Link])

43. Hamill N, Rijhsinghani A, Williamson RA, et al. Prenatal diagnosis and management of fetal anemia
secondary to a large chorioangioma. Obstet Gynecol. 2003 Nov;102(5 Pt 2):1185-8. Abstract (http://
[Link]/pubmed/14607051?tool=[Link])

44. El Kateb A, Ville Y. Update on twin-to-twin transfusion syndrome. Best Pract Res Clin Obstet
Gynaecol. 2008 Feb;22(1):63-75. Abstract ([Link]
tool=[Link])

45. Baschat AA, Oepkes D. Twin anemia-polycythemia sequence in monochorionic twins: implications
for diagnosis and treatment. Am J Perinatol. 2014 Sep;31(1 suppl):S25-30. Abstract (http://
[Link]/pubmed/24858317?tool=[Link])

46. Visser GHA, Thommesen T, Di Renzo GC, et al. FIGO/ICM guidelines for preventing Rhesus disease:
a call to action. Int J Gynaecol Obstet. 2021 Feb;152(2):144-7. Full text ([Link]
pmc/articles/PMC7898700) Abstract ([Link]
tool=[Link])

47. Okwundu CI, Afolabi BB. Intramuscular versus intravenous anti-D for preventing Rhesus
alloimmunization during pregnancy. Cochrane Database Syst Rev. 2013 Jan 31;(1):CD007885. Full
text ([Link] Abstract
([Link]

48. Pollack W, Ascari WQ, Kochesky RJ, et al. Studies on Rh prophylaxis. 1. Relationship between doses
of anti-Rh and size of antigenic stimulus. Transfusion. 1971 Nov-Dec;11(6):333-9. Abstract (http://
[Link]/pubmed/5002765?tool=[Link])

49. Fung MK, Grossman BJ, Hillyer CD, et al, eds. Technical manual. 18th ed. Bethesda (MD): American
Association of Blood Banks; 2014.

50. National Blood Authority. Prophylactic use of Rh D immunoglobulin in pregnancy care. 2021 [internet
publication]. Full text ([Link]

51. McBain RD, Crowther CA, Middleton P. Anti-D administration in pregnancy for preventing Rhesus
alloimmunisation. Cochrane Database Syst Rev. 2015 Sep 3;(9):CD000020. Full text (https://
[Link]/cdsr/doi/10.1002/14651858.CD000020.pub3/full) Abstract (http://
[Link]/pubmed/26334436?tool=[Link])

52. Royal College of Obstetricians and Gynaecologists. The management of women with red cell
antibodies during pregnancy: green-top guideline no 65. May 2014 [internet publication]. Full text
([Link]

40 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 11, 2025.
BMJ Best Practice topics are regularly updated and the most recent version of the topics
can be found on [Link] . Use of this content is subject to our disclaimer (.
Use of this content is subject to our) . © BMJ Publishing Group Ltd 2025. All rights reserved.
Rh incompatibility References
53. National Institute for Health and Care Excellence. Ectopic pregnancy and miscarriage: diagnosis and
initial management. Nov 2021 [internet publication]. Full text ([Link]

REFERENCES
54. Li MJ, Chen CH, Wu Q, et al. Intravenous immunoglobulin G for hemolytic disease of the newborn:
a systematic review [in Chinese]. Chin J Evid Based Med. 2010;10:1199-204. Full text (http://
[Link]/Article_en/[Link])

55. Huizing K, Røislien J, Hansen T. Intravenous immunoglobulin reduces the need for exchange
transfusion in Rhesus and ABO incompatibility. Acta Paediatr. 2008 Oct;97(10):1362-5. Abstract
([Link]

56. Smits-Wintjens VE, Walther FJ, Rath ME, et al. Intravenous immunoglobulin in neonates with rhesus
hemolytic disease: a randomized controlled trial. Pediatrics. 2011 Apr;127(4):680-6. Abstract (http://
[Link]/pubmed/21422084?tool=[Link])

57. Zwiers C, Scheffer-Rath ME, Lopriore E, et al. Immunoglobulin for alloimmune hemolytic disease
in neonates. Cochrane Database Syst Rev. 2018 Mar 18;(3):CD003313. Full text (https://
[Link]/cdsr/doi/10.1002/14651858.CD003313.pub2/full) Abstract (http://
[Link]/pubmed/29551014?tool=[Link])

58. [Link]. A study to evaluate the safety, efficacy, pharmacokinetics and pharmacodynamics
of M281 administered to pregnant women at high risk for early onset severe hemolytic disease of the
fetus and newborn (HDFN). Jan 2023 [internet publication]. Full text ([Link]
NCT03842189)

59. Matsuda H, Yoshida M, Wakamatsu H, et al. Fetal intraperitoneal injection of immunoglobulin

diminishes alloimmune hemolysis. J Perinatol. 2011 Apr;31(4):289-92. Abstract (http://
[Link]/pubmed/21448182?tool=[Link])

60. Bellone M, Boctor FN. Therapeutic plasma exchange and intravenous immunoglobulin as primary
therapy for D alloimmunization in pregnancy precludes the need for intrauterine transfusion.
Transfusion. 2014 Aug;54(8):2118-21. Abstract ([Link]
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61. Kriplani A, Malhotra Singh B, Mandal K. Fetal intravenous immunoglobulin therapy in rhesus
hemolytic disease. Gynecol Obstet Invest. 2007;63(3):176-80. Abstract ([Link]
pubmed/17143009?tool=[Link])

62. Katz MA, Kanto WP Jr, Korotkin JH. Recurrence rate of ABO hemolytic disease of the newborn.
Obstet Gynecol. 1982 May;59(5):611-4. Abstract ([Link]
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63. Smits-Wintjens VE, Walther FJ, Lopriore E. Rhesus haemolytic disease of the newborn:
postnatal management, associated morbidity and long-term outcome. Semin Fetal Neonatal
Med. 2008 Aug;13(4):265-71. Abstract ([Link]
tool=[Link])

65. Weiner CP, Williamson RA, Wenstrom KD, et al. Management of fetal hemolytic disease by
cordocentesis. I. Prediction of fetal anemia. Am J Obstet Gynecol. 1991 Sep;165(3):546-53. Abstract
([Link]

66. Lindenburg IT, Smits-Wintjens VE, van Klink JM, et al; LOTUS study group. Long-term
neurodevelopmental outcome after intrauterine transfusion for hemolytic disease of the fetus/
newborn: the LOTUS study. Am J Obstet Gynecol. 2012 Feb;206(2):141.e1-8. Full text (https://
[Link]/article/S0002-9378%2811%2901211-7/fulltext) Abstract ([Link]
pubmed/22030316?tool=[Link])

42 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 11, 2025.
BMJ Best Practice topics are regularly updated and the most recent version of the topics
can be found on [Link] . Use of this content is subject to our disclaimer (.
Use of this content is subject to our) . © BMJ Publishing Group Ltd 2025. All rights reserved.
Rh incompatibility Images

Images

IMAGES
Figure 1: Increased velocity in the middle cerebral artery consistent with severe fetal anaemia
The Ottawa Hospital; used with consent of the patient

Figure 2: Fetal hydrops, with ascites and hepatomegaly (arrow) diagnosed on antenatal ultrasound
The Ottawa Hospital; used with consent of the patient

44 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 11, 2025.
BMJ Best Practice topics are regularly updated and the most recent version of the topics
can be found on [Link] . Use of this content is subject to our disclaimer (.
Use of this content is subject to our) . © BMJ Publishing Group Ltd 2025. All rights reserved.
Rh incompatibility Images

IMAGES
Figure 3: Intraperitoneal transfusion; the echogenic needle tip is visualised in the pocket of ascites
The Ottawa Hospital; used with consent of the patient

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// Authors:

Andrew D. Hull, MD, FRCOG, FACOG

Professor of Clinical Obstetrics, Gynecology, and Reproductive Sciences
Director, UC San Diego Maternal-Fetal Care and Genetics, Division of Maternal-Fetal Medicine, Department
of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Diego, La Jolla, CA
DISCLOSURES: ADH declares that he has no competing interests.

// Acknowledgements:
Dr Andrew D. Hull would like to gratefully acknowledge Dr Karen Fung-Kee-Fung and Dr Felipe Moretti,
previous contributors to this topic.
DISCLOSURES: KFKF is an author of a reference cited in this topic. KFKF and FM declare that they have
no competing interests.

// Peer Reviewers:

Alan Cameron, MD
Honorary Professor of Medicine
University of Glasgow, Glasgow, UK
DISCLOSURES: AC is an author of several references cited in this topic.

Liakat Ali Parapia, MD, FRCP

Consultant Hematologist
Bradford Teaching Hospitals NHS Trust, Yorkshire Clinic, Bingley, Bradford, UK
DISCLOSURES: LAP declares that he has no competing interests.

Kenneth J. Moise, Jr., MD

Professor of Obstetrics and Gynecology
Texas Children's Fetal Center, Baylor College of Medicine/Texas Children's Hospital, Houston, TX
DISCLOSURES: KJM declares that he has no competing interests.

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